The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.
Hirschsprung disease (HSCR) is a multigenic neurocristopathy clinically recognized by aganglionosis of the distal gastrointestinal tract. Patients presenting with aganglionosis in association with hypopigmentation are classified as Waardenburg syndrome type 4 (Waardenburg-Shah, WS4). Variability in the disease phenotype of WS4 patients with equivalent mutations suggests the influence of genetic modifier loci in this disorder. Sox10(Dom)/+ mice exhibit variability of aganglionosis and hypopigmentation influenced by genetic background similar to that observed in WS4 patients. We have constructed Sox10(Dom)/+ congenic lines to segregate loci that modify the neural crest defects in these mice. Consistent with previous studies, increased lethality of Sox10(Dom)/+ animals resulted from a C57BL/6J locus(i). However, we also observed an increase in hypopigmentation in conjunction with a C3HeB/FeJLe-a/a locus(i). Linkage analysis localized a hypopigmentation modifier of the Dom phenotype to mouse chromosome 10 in close proximity to a previously reported modifier of hypopigmentation for the endothelin receptor B mouse model of WS4. To evaluate further the role of SOX10 in development and disease, we have performed comparative genomic analyses. An essential role for this gene in neural crest development is supported by zoo blot hybridizations that reveal extensive conservation throughout vertebrate evolution and by similar Northern blot expression profiles between mouse and man. Comparative sequence analysis of the mouse and human SOX10 gene have defined the exon-intron boundaries of SOX10 and facilitated mutation analysis leading to the identification of two new SOX10 mutations in individuals with WS4. Structural analysis of the HMG DNA-binding domain was performed to evaluate the effect of human mutations in this region.


Heterochromatin on the inactive X chromosome delays replication timing without affecting origin usage.
DNA replication origins (ORIs) map close to promoter regions in many organisms, including mammals. However, the relationship between initiation of replication and transcription is not well understood. To address this issue, we have analyzed replication timing and activity of several CpG island-associated ORIs on the transcriptionally active and silent X chromosomes. We find equivalent ORI usage and efficiency of both alleles at sites that are replicated late on the inactive X chromosome. Thus, in contrast to its repressive effect on transcription, heterochromatin does not influence ORI activity. These findings suggest that the relationship between sites of transcription and replication initiation at CpG island regions is restricted to early development, and that subsequent gene silencing and heterochromatin formation influence only the timing of ORI activation.


High glucose attenuates shear-induced changes in endothelial hydraulic conductivity by degrading the glycocalyx.
Diabetes mellitus is a risk factor for cardiovascular disease; however, the mechanisms through which diabetes impairs homeostasis of the vasculature have not been completely elucidated. The endothelium interacts with circulating blood through the surface glycocalyx layer, which serves as a mechanosensor/transducer of fluid shear forces leading to biomolecular responses. Atherosclerosis localizes typically in regions of low or disturbed shear stress, but in diabetics, the distribution is more diffuse, suggesting that there is a fundamental difference in the way cells sense shear forces. In the present study, we examined the effect of hyperglycemia on mechanotranduction in bovine aortic endothelial cells (BAEC). After six days in high glucose media, we observed a decrease in heparan sulfate content coincident with a significant attenuation of the shear-induced hydraulic conductivity response, lower activation of eNOS after exposure to shear, and reduced cell alignment with shear stress. These studies are consistent with a diabetes-induced change to the glycocalyx altering endothelial response to shear stress that could affect the distribution of atherosclerotic plaques.


A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01.
In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial. A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen. A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.


Epithelial and endothelial damage induced by mechanical ventilation modes.
The adult respiratory distress syndrome (ARDS) is a common cause of respiratory failure with substantial impact on public health. Patients with ARDS generally require mechanical ventilation, which risks further lung damage. Recent improvements in ARDS outcomes have been attributed to reductions in deforming stress associated with lung protective mechanical ventilation modes and settings. The following review details the mechanics of the lung parenchyma at different spatial scales and the response of its resident cells to deforming stress in order to provide the biologic underpinnings of lung protective care. Although lung injury is typically viewed through the lens of altered barrier properties and mechanical ventilation-associated immune responses, in this review, we call attention to the importance of heterogeneity and the physical failure of the load bearing cell and tissue elements in the pathogenesis of ARDS. Specifically, we introduce a simple elastic network model to better understand the deformations of lung regions, intra-acinar alveoli and cells within a single alveolus, and consider the role of regional distension and interfacial stress-related injury for various ventilation modes. Heterogeneity of stiffness and intercellular and intracellular stress failure are fundamental components of ARDS and their development also depends on the ventilation mode.


Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover.
Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX-1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX-1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases.


Nurse competence: advantageous in pre-hospital emergency care?
Aspects of the organization and function of pre-hospital emergency care services in western Sweden were assessed by interviewing physicians (n = 20) with administrative (n = 10) or/and active (n = 10) roles in the pre-hospital emergency care field. The data obtained indicate that although the present standard of care is acceptable, there is an obvious need for a more effective organization and the personnel involved should have a higher competence level. Ambulance personnel were not considered to have a high enough competence level. Therefore, a need for more nurses, preferably anaesthesia or intensive care nurses, was expressed. An awareness of the importance of research was noted among the physicians responsible for the services, and the research capability of nurses, along with their general competence in emergency medical service related problems, was considered an important argument for involving more nurses in pre-hospital emergency care. It was thought that by such an approach, a more scientific basis for assessing the efficacy of pre-hospital emergency care could be achieved.


Continuous monitoring and intrafraction target position correction during treatment improves target coverage for patients undergoing SBRT prostate therapy.
To compare the potential benefits of continuous monitoring of prostate position and intervention (CMI) using 2-mm displacement thresholds during stereotactic body radiation therapy (SBRT) treatment to those of a conventional image-guided procedure involving single localization prior to treatment. Eighty-nine patients accrued to a prostate SBRT dose escalation protocol were implanted with radiofrequency transponder beacons. The planning target volume (PTV) margin was 5 mm in all directions, except for 3 mm in the posterior direction. The prostate was kept within 2 mm of its planned position by the therapists halting dose delivery and, if necessary, correcting the couch position. We computed the number, type, and time required for interventions and where the prostate would have been during dose delivery had there been, instead, a single image-guided setup procedure prior to each treatment. Distributions of prostate displacements were computed as a function of time. After the initial setup, 1.7 interventions per fraction were required, with a concomitant increase in time for dose delivery of approximately 65 seconds. Small systematic drifts in prostate position in the posterior and inferior directions were observed in the study patients. Without CMI, intrafractional motion would have resulted in approximately 10% of patients having a delivered dose that did not meet our clinical coverage requirement, that is, a PTV D95 of >90%. The posterior PTV margin required for 95% of the dose to be delivered with the target positioned within the PTV was computed as a function of time. The margin necessary was found to increase by 2 mm every 5 minutes, starting from the time of the imaging procedure. CMI using a tight 2-mm displacement threshold was not only feasible but was found to deliver superior PTV coverage compared with the conventional image-guided procedure in the SBRT setting.


Cardiac xenografts between primate species provide evidence for the importance of the alpha-galactosyl determinant in hyperacute rejection.
Transplants performed between phylogenetically disparate species are subject to hyperacute rejection initiated by binding of xenoreactive natural Abs to endothelium in the donor organ. Binding of these Abs activates complement, leading to tissue injury and destruction of the graft. Human xenoreactive natural Abs recognize Gal alpha 1-3Gal beta 1-4GlcNAc (galactose alpha 1-3galactose beta 1-4-N-acetylglucosame); however, the relative importance of this Ag in graft rejection has not been proved. The present study was conducted to test the potential importance of alpha-galactosyl (alpha-Gal) determinants in the pathogenesis of hyperacute rejection. To this end, hearts (n = 3) from New World monkeys (Saimiri scureus, squirrel monkey), which can synthesize Gal alpha 1-3Gal, were transplanted heterotopically into Old World monkeys (Papio species, baboon), which do not synthesize Gal alpha 1-3Gal determinants and which have circulating anti-alpha Gal Abs. The xenografts were rejected in 51 to 56 min (mean +/- SD = 53.3 +/- 2.5), results similar to those observed in porcine grafts transplanted into baboons. Histologic analysis of the hearts revealed thrombosis and intraparenchymal hemorrhage and immune deposits consisting of IgM, Clq, C3, C4, C5b, and the membrane attack complex, but not properdin or factor B of the recipient deposited on graft endothelium. Sera obtained from baboons after perfusion of squirrel monkey kidneys revealed depletion of alpha-Gal-specific Abs and anti-pig endothelial cell Abs. These findings provide strong evidence that the Abs that accumulate in New World monkey organs during perfusion with baboon blood are the same Abs that would accumulate in a porcine organ transplanted into a primate and suggest that hyperacute rejection is not necessarily a reflection of phylogenetic distance but that the expression of terminal alpha-Gal residues provides an adequate target to initiate that process.


New design for photonic temporal integration with combined high processing speed and long operation time window.
We propose and experimentally prove a novel design for implementing photonic temporal integrators simultaneously offering a high processing bandwidth and a long operation time window, namely a large time-bandwidth product. The proposed scheme is based on concatenating in series a time-limited ultrafast photonic temporal integrator, e.g. implemented using a fiber Bragg grating (FBG), with a discrete-time (bandwidth limited) optical integrator, e.g. implemented using an optical resonant cavity. This design combines the advantages of these two previously demonstrated photonic integrator solutions, providing a processing speed as high as that of the time-limited ultrafast integrator and an operation time window fixed by the discrete-time integrator. Proof-of-concept experiments are reported using a uniform fiber Bragg grating (as the original time-limited integrator) connected in series with a bulk-optics coherent interferometers' system (as a passive 4-points discrete-time photonic temporal integrator). Using this setup, we demonstrate accurate temporal integration of complex-field optical signals with time-features as fast as ~6 ps, only limited by the processing bandwidth of the FBG integrator, over time durations as long as ~200 ps, which represents a 4-fold improvement over the operation time window (~50 ps) of the original FBG integrator.


Loss of culturability of Salmonella enterica subsp. enterica serovar Typhimurium upon cell-cell contact with human fecal bacteria.
Loss of culturability of Salmonella enterica subsp. enterica serovar Typhimurium has been observed in mixed cultures with anaerobic fecal bacteria under conditions that allow local interaction between cells, such as cell contact. A reduction of a population of culturable S. Typhimurium on the order of ∼10(4) to 10(5) CFU/ml was observed in batch anaerobic mixed cultures with fecal samples from different human donors. Culturability was not affected either in supernatants collected at several times from fecal cultures, when separated from fecal bacteria by a membrane of 0.45-μm pore size, or when in contact with inactivated fecal bacterial cells. Loss of culturability kinetics was characterized by a sharp reduction of several logarithmic units followed by a pronounced tail. A mathematical model was developed to describe the rate of loss of culturability as a function of the frequency of encounters between populations and the probability of inactivation after encounter. The model term F(S · F)(1/2) quantifies the effect of the concentration of both populations, fecal bacteria (F) and S. Typhimurium (S), on the loss of culturability of S. Typhimurium by cell contact with fecal bacteria. When the value of F(S · F)(1/2) decreased below ca. 10(15) (CFU/ml)(2), the frequency of encounters sharply decreased, leading to the deceleration of the inactivation rate and to the tailing off of the S. Typhimurium population. The probability of inactivation after encounter, P, was constant, with an estimated value of ∼10(-5) for all data sets. P might be characteristic of the mechanism of growth inhibition after a cell encounter.


Temazepam and the perceptual-motor performance of professional footballers.
The use of benzodiazepines to overcome the possible debilitating effects of travel on football performance is a recent phenomenon and indicative of current usage of such drugs. Contemporary psychological theory is critical of many of the measures used to monitor such drugs. This study has created a battery of tests which include some measures which are deemed more ecologically valid and, for purposes of comparison, some traditional indices. On a sample of First Division professional Association footballers temazepam (40 mg) was compared with placebo on these measures and testing occurred on the afternoon following night time medication. The findings suggest that on such a protocol, perceptual-motor performance is not impaired.


Deliberating the Diagnostic Dilemma of Heart Failure With Preserved Ejection Fraction.
There is a lack of consensus on how we define heart failure with preserved ejection fraction (HFpEF), with wide variation in diagnostic criteria across society guidelines. This lack of uniformity in disease definition stems in part from an incomplete understanding of disease pathobiology, phenotypic heterogeneity, and natural history. We review current knowledge gaps and existing diagnostic tools and algorithms. We present a simple approach to implement these tools within the constraints of the current knowledge base, addressing separately (1) hospitalized individuals with rest congestion, where diagnosis is more straightforward; and (2) individuals with exercise intolerance, where diagnosis is more complex. Here, a potential role for advanced or provocative testing, including evaluation of hemodynamic responses to exercise is considered. More importantly, we propose focus areas for future studies to develop accurate and feasible diagnostic tools for HFpEF, including animal models that recapitulate human HFpEF, and human studies that both address a fundamental understanding of HFpEF pathobiology, and new diagnostic approaches and tools, as well. In sum, there is an urgent need to more accurately define the syndrome of HFpEF to inform diagnosis, patient selection for clinical trials, and, ultimately, future therapeutic approaches.


Why vision is not both hierarchical and feedforward.
In classical models of object recognition, first, basic features (e.g., edges and lines) are analyzed by independent filters that mimic the receptive field profiles of V1 neurons. In a feedforward fashion, the outputs of these filters are fed to filters at the next processing stage, pooling information across several filters from the previous level, and so forth at subsequent processing stages. Low-level processing determines high-level processing. Information lost on lower stages is irretrievably lost. Models of this type have proven to be very successful in many fields of vision, but have failed to explain object recognition in general. Here, we present experiments that, first, show that, similar to demonstrations from the Gestaltists, figural aspects determine low-level processing (as much as the other way around). Second, performance on a single element depends on all the other elements in the visual scene. Small changes in the overall configuration can lead to large changes in performance. Third, grouping of elements is key. Only if we know how elements group across the entire visual field, can we determine performance on individual elements, i.e., challenging the classical stereotypical filtering approach, which is at the very heart of most vision models.


Physical and mental health of children with substantiated sexual abuse: Gender comparisons from a matched-control cohort study.
When compared to children from the general population, sexually abused children receive more medical services, both for physical and mental health problems. However, possible differences between sexually abused boys and girls remain unknown. The lack of control group in studies that find gender differences also prevents from determining if the differences are specific to sexual abuse or to gender. The objective of the study was to assess differences in physical and mental health between sexually abused boys and girls in comparison to those from the general population. Administrative databases were used to document physical and mental health problems of 222 males and 660 females with a substantiated report of sexual abuse between 2001 and 2010. A comparison group individually matched to those from the sexually abused group on gender, age and geographic area was also used to document gender differences in the general population. Yearly incidence rates of diagnoses resulting from medical consultations and hospitalizations of males and females were compared over five years after a first substantiated sexual abuse report using the mixed general linear model. Sexually abused girls were up to 2.2 times more likely to consult a physician than sexually abused boys for physical health problems. Similar findings are observed in the general population. Conversely, results revealed that sexually abused boys were up to 2.3 times more likely than females to consult a physician for mental health problems. This gender difference was not apparent in the general population group.


A single-arm feasibility study of community-delivered Baduanjin (Qigong practice of the eight Brocades) training for frail older adults.
Frailty is a common geriatric syndrome, characterized by reduced physiologic reserve and increased vulnerability to stressors, due to cumulative decline in multiple physiological systems. We studied the feasibility of a community-delivered Baduanjin (BDJ) training program among pre-frail/frail community-dwelling older people. We examined (1) safety (adverse events) and physical and psychological effects; and (2) feasibility of recruitment, retention, adherence; recruitment efforts, and any program challenges, so as to inform future studies. Our study was a single arm pre-post study in a community setting. Sixteen-week group BDJ training (2×/week in the first 4 weeks and 3×/week thereafter) was co-designed and implemented by community-based providers in Singapore. Recruitment, attendance, and adverse events were recorded throughout the training. A participants' survey was also administered after the training program. Effects of the intervention on physical and functional outcomes (hand grip strength, knee extension strength, Time Up and Go (TUG), Physiological Profile Assessment (PPA), 30-s Sit-to-Stand test, 6-m fast gait speed test), frailty outcomes (frailty score and status), and other outcomes (Maastricht Questionnaire (MQ), Fall Efficacy Scale (FES), Montreal Cognitive Assessment (MoCA), Geriatric Depression Scale (GDS), and EQ-5D-5L) were examined before and after the program. Of 31 older adults screened to be frail, 15 met inclusion criteria and 3 refused participation, resulting in 12 older adults (9 women) enrolled into the program. During the program, one participant was hospitalized (unrelated to BDJ training) and the other 11 (aged 77 ± 6 years; 2 frail, 9 prefrail at baseline) completed the program with average overall attendance of 89%. Most (89%) of the 44 training sessions had attendance > 80%. The program received positive feedback with no training-related adverse events. Participants either reversed (n = 2) or maintained (n = 9) their frailty statuses. There post-training outcomes in hand grip strength, knee extension strength, TUG, MQ, FES, MoCA, GDS, and EQ-5D-5L index score appeared to be better. The reduction of frailty and PPA fall risk scores was of moderate-to-large effect size. Community-delivered BDJ training program was safe and feasible for prefrail/frail older adults with the potential to improve physical and cognitive function, reduce fall risk, improve psychological well-being, and reverse frailty status.


First case of Anaplasma platys infection in a dog from Croatia.
It is known that Anaplasma (A.) platys, the causative agent of infectious canine cyclic thrombocytopenia, is endemic in countries of the Mediterranean basin. However, few reports are available from the Balkans. This case report describes a dog, which was imported from Croatia to Germany in May 2010. One month later the dog was presented to a local veterinarian in Germany due to intermittent/recurrent diarrhoea. Diagnostic tests were performed to identify infections caused by Anaplasma spp., Ehrlichia spp., Hepatozoon canis, Babesia spp., Leishmania spp., Borrelia burgdorferi and/or Dirofilaria immitis. Haematological examination of a blood smear revealed basophilic inclusions in thrombocytes, which were confirmed as A. platys with a species-specific real-time PCR. Additionally, an infection with Babesia (B.) vogeli was also detected (PCR and serology). No specific antibodies against Anaplasma antigen were detectable. Although the dog showed no specific clinical signs, thrombocytopenia, anaemia and elevated C-reactive protein (CRP) were observed. Sequencing of a 1,348-bp partial ribosomal RNA gene revealed highest homology to A. platys sequences from Thailand, Japan and France. A. platys was detected for first time in a dog imported from Croatia. As the dog was also co-infected by B. vogeli, unique serological and haematological findings were recorded. Thrombocytopenia, anaemia and elevated values of C-reactive protein were the laboratory test abnormalities observed in this case. A. platys infections should be considered in dogs coming from Croatia and adjacent regions.


RNA-sequencing from single nuclei.
It has recently been established that synthesis of double-stranded cDNA can be done from a single cell for use in DNA sequencing. Global gene expression can be quantified from the number of reads mapping to each gene, and mutations and mRNA splicing variants determined from the sequence reads. Here we demonstrate that this method of transcriptomic analysis can be done using the extremely low levels of mRNA in a single nucleus, isolated from a mouse neural progenitor cell line and from dissected hippocampal tissue. This method is characterized by excellent coverage and technical reproducibility. On average, more than 16,000 of the 24,057 mouse protein-coding genes were detected from single nuclei, and the amount of gene-expression variation was similar when measured between single nuclei and single cells. Several major advantages of the method exist: first, nuclei, compared with whole cells, have the advantage of being easily isolated from complex tissues and organs, such as those in the CNS. Second, the method can be widely applied to eukaryotic species, including those of different kingdoms. The method also provides insight into regulatory mechanisms specific to the nucleus. Finally, the method enables dissection of regulatory events at the single-cell level; pooling of 10 nuclei or 10 cells obscures some of the variability measured in transcript levels, implying that single nuclei and cells will be extremely useful in revealing the physiological state and interconnectedness of gene regulation in a manner that avoids the masking inherent to conventional transcriptomics using bulk cells or tissues.


Hereditary haemorragic teleangectasia and pregnancy: case report.
We report an uncommon case of a 38-years-old pregnant woman affected by HHT (Hereditary haemorrhagic telangiectasia; Osler-Weber-Rendu syndrome) who underwent to a caesarean section (CS) without any complication. The patient at 36th weeks+1 day pregnancy referred to the Emergency Obstetric Unit due to a intercostals pain on left side. On third day after admission the woman started travailing and physicians decided to perform the CS. Considering that no AVMs was found at MRI, a continuous spinal anaesthesia was planned. On postpartum day 4 the patient was discharged. This represents the only case published in the literature. Women with HHT, especially those with arteriovenous malformations (AVM), are at high risk in pregnancy due to physiological haemodynamic changes pregnancy associated. Early screening of patients with HHT for the presence of spinal cord or cerebral AVMs is recommended to optimise perioperative anaesthetic management and to avoid severe complications.


Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation.
Prostaglandin E(2) (PGE(2)) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE(2) generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE(2)-deficient ptges(-/-) mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE(2)-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE(2) deficiency depend on thromboxane A(2) and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges(-/-) mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)(1) and EP(2) receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE(2) deficiency. Thus, PGE(2) controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.


Neutrophil Extracellular Traps Enhance Staphylococcus Aureus Vegetation Formation through Interaction with Platelets in Infective Endocarditis.
The mechanisms or host factors involved in septic thrombus or vegetation formation in Staphylococcus aureus-induced infective endocarditis (IE) are unclear. Using an experimental endocarditis rat model, here we demonstrated that S. aureus HG001-induced vegetation was composed of bacterial floes encased in aggregated platelets and surrounded by neutrophil extracellular traps (NETs). In vitro data demonstrated that platelets contribute to both biofilm and NET formation. Prophylactic administration of DNase I significantly reduced the size of vegetation induced by methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) strains, even though MRSA and MSSA isolates express different biofilm phenotypes and NET-induction abilities in the presence of platelets. Moreover, delivery of both DNase I and daptomycin prophylactically and therapeutically produced synergistic effects by reducing vegetation size and bacterial numbers on damaged valve tissues in MRSA-induced IE. Together, these data suggest that NETs contribute to vegetation formation in S. aureus endocarditis and DNase I has the potential to control S. aureus-induced IE in the clinic.


Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer.
Selective lymphadenectomy is widely accepted in the management of endometrial cancer. Purported benefits are individualization of adjuvant therapy based on extent of disease and resection of occult metastases. Our goal was to assess effects of the extent of selective lymphadenectomy on outcomes in women with apparent stage I endometrial cancer at laparotomy. Patients with endometrial cancer who received primary surgical treatment between 1973 and 2002 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/IIA disease and procedure including hysterectomy and selective lymphadenectomy (pelvic or pelvic + aortic). Exclusion criteria included presurgical radiation, grossly positive lymph nodes, or extrauterine metastases at laparotomy. Recurrence and survival were analyzed using Kaplan-Meier analysis and Cox proportional hazards model. Among 509 patients, the median number of lymph nodes removed was 15 (median pelvic, 11; median aortic, three). Pelvic and aortic node metastases were found in 24 (5%) of 509 patients and 11 (3%) of 373 patients, respectively. Patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Number of nodes removed was not predictive of survival among patients with cancers of grade 1 to 2. Performance of aortic selective lymphadenectomy was not associated with survival. Three (27%) of 11 patients with microscopic aortic nodal metastasis are alive without recurrence. These data add to the literature documenting the possible therapeutic benefit of selective lymphadenectomy in management of patients with apparent early-stage endometrial cancer.


Propulsion (mass movements) in the human colon and its relationship to meals and somatic activity.
Propulsive activity of the human colon was measured with radiopaque markers (shapes), radiotelemetering capsules, Perspex capsules containing (51)Cr, or with free (51)Cr sodium chromate. Propulsive activity can be readily detected by these techniques, none of which requires the use of radiological contrast media. With capsules containing (51)Cr or with free (51)Cr repeated observations can be made in the same patient without recourse to radiography. The patient can remain normally active during the test with encapsulated (51)Cr. Repeated observations may also be made with shapes, if films exposed at low mA are used. It was found that colonic intraluminal pressure activity rises markedly during and after food, but that in the resting patient this increase is rarely associated with propulsive activity. In physically active patients propulsion of colonic contents was significantly increased after meals. When colonic propulsion takes place, it does so by a series of mass movements. These results suggest that somatic activity is an important factor in the control of colonic transit in health or disease.


GMP-compliant isolation and large-scale expansion of bone marrow-derived MSC.
Mesenchymal stromal cells (MSC) have gained importance in tissue repair, tissue engineering and in immunosupressive therapy during the last years. Due to the limited availability of MSC in the bone marrow, ex vivo amplification prior to clinical application is requisite to obtain therapeutic applicable cell doses. Translation of preclinical into clinical-grade large-scale MSC expansion necessitates precise definition and standardization of all procedural parameters including cell seeding density, culture medium and cultivation devices. While xenogeneic additives such as fetal calf serum are still widely used for cell culture, its use in the clinical context is associated with many risks, such as prion and viral transmission or adverse immunological reactions against xenogeneic components. We established animal-free expansion protocols using platelet lysate as medium supplement and thereby could confirm its safety and feasibility for large-scale MSC isolation and expansion. Five different GMP-compliant standardized protocols designed for the safe, reliable, efficient and economical isolation and expansion of MSC was performed and MSC obtained were analyzed for differentiation capacity by qPCR and histochemistry. Expression of standard MSC markers as defined by the International Society for Cellular Therapy as well as expression of additional MSC markers and of various chemokine and cytokine receptors was analysed by flow cytometry. Changes of metabolic markers and cytokines in the medium were addressed using the LUMINEX platform. The five different systems for isolation and expansion of MSC described in this study are all suitable to produce at least 100 millions of MSC, which is commonly regarded as a single clinical dose. Final products are equal according to the minimal criteria for MSC defined by the ISCT. We showed that chemokine and integrin receptors analyzed had the same expression pattern, suggesting that MSC from either of the systems show equal characteristics of homing and adhesion.


Caveolae-dependent and -independent uptake of albumin in cultured rodent pulmonary endothelial cells.
Although a critical role for caveolae-mediated albumin transcytosis in pulmonary endothelium is well established, considerably less is known about caveolae-independent pathways. In this current study, we confirmed that cultured rat pulmonary microvascular (RPMEC) and pulmonary artery (RPAEC) endothelium endocytosed Alexa488-labeled albumin in a saturable, temperature-sensitive mode and internalization resulted in co-localization by fluorescence microscopy with cholera B toxin and caveolin-1. Although siRNA to caveolin-1 (cav-1) in RPAEC significantly inhibited albumin uptake, a remnant portion of albumin uptake was cav-1-independent, suggesting alternative pathways for albumin uptake. Thus, we isolated and cultured mouse lung endothelial cells (MLEC) from wild type and cav-1(-/-) mice and noted that ~ 65% of albumin uptake, as determined by confocal imaging or live cell total internal reflectance fluorescence microscopy (TIRF), persisted in total absence of cav-1. Uptake of colloidal gold labeled albumin was evaluated by electron microscopy and demonstrated that albumin uptake in MLEC from cav-1(-/-) mice was through caveolae-independent pathway(s) including clathrin-coated pits that resulted in endosomal accumulation of albumin. Finally, we noted that albumin uptake in RPMEC was in part sensitive to pharmacological agents (amiloride [sodium transport inhibitor], Gö6976 [protein kinase C inhibitor], and cytochalasin D [inhibitor of actin polymerization]) consistent with a macropinocytosis-like process. The amiloride sensitivity accounting for macropinocytosis also exists in albumin uptake by both wild type and cav-1(-/-) MLEC. We conclude from these studies that in addition to the well described caveolar-dependent pulmonary endothelial cell endocytosis of albumin, a portion of overall uptake in pulmonary endothelial cells is cav-1 insensitive and appears to involve clathrin-mediated endocytosis and macropinocytosis-like process.


Raman spectroscopy application in frozen carrot cooked in different ways and the relationship with carotenoids.
Raman spectroscopy, in its confocal micro-Raman variation, has been recently proposed as a spatially resolved method to identify carotenoids in various food matrices, being faster, non-destructive, and avoiding sample extraction, but no data are present in the literature concerning its application to the evaluation of carotenoid pattern changes after thermal treatment of carrots. The effect of three cooking methods (i.e. boiling, steaming and microwaving) was evaluated on frozen carrot, comparing changes on carotenoid profiles measured by means of Raman spectroscopy with their high-performance liquid chromatographic determination and colour. A more pronounced detrimental effect on carotenoids was detected in steamed carrots, in accordance with colour data. Conversely, boiling and, to a lesser extent, microwaving caused an increase in carotenoid concentration. Cooking procedures affected the Raman spectral features of carotenoids, causing a shift of vibration frequencies towards a higher energy, increase in the spectral baseline and peak intensities as well as a broadening of their width, probably in relation to the thermal degradation of longer carotenoids (i.e. the all-trans form) and the isomerization process. In particular, steamed samples showed a significantly higher increase of centre frequency, in accordance with a more pronounced isomerization and changes in colour parameters. This work showed that the evolution of Raman spectral parameters could provide information on carotenoid bioaccessibility for carrots cooked using various methods. This paves the way for a future use of this technique to monitor and optimize cooking processes aimed at maximizing carotenoid bioaccessibility and bioavailability.


Randomized 52-week Phase 2 Trial of Albiglutide Versus Placebo in Adult Patients With Newly Diagnosed Type 1 Diabetes.
GLP-1 receptor agonists are an established therapy in patients with type 2 diabetes; however, their role in type 1 diabetes remains to be determined. Determine efficacy and safety of once-weekly albiglutide 30 mg (up-titration to 50 mg at week 6) versus placebo together with insulin in patients with new-onset type 1 diabetes and residual insulin production. 52-week, randomized, phase 2 study (NCT02284009). A prespecified Bayesian approach, incorporating placebo data from a prior study, allowed for 3:1 (albiglutide:placebo) randomization. The primary endpoint was 52-week change from baseline in mixed meal tolerance test (MMTT) stimulated 2-h plasma C-peptide area under the curve (AUC). Secondary endpoints included metabolic measures and pharmacokinetics of albiglutide. 12/17 (70.6%, placebo) and 40/50 (80.0%, albiglutide) patients completed the study. Within our study, mean (standard deviation) change from baseline to week 52 in MMTT-stimulated 2-h plasma C-peptide AUC was -0.16 nmol/L (0.366) with placebo and -0.13 nmol/L (0.244) with albiglutide. For the primary Bayesian analysis (including prior study data) the posterior treatment difference (95% credible interval) was estimated at 0.12 nmol/L (0-0.24); the probability of a difference ≥0.2 nmol/L between treatments was low (0.097). A transient significant difference in maximum C-peptide was seen at week 28. Otherwise, no significant secondary endpoint differences were noted. On-therapy adverse events were reported in 82.0% (albiglutide) and 76.5% (placebo) of patients. In newly diagnosed patients with type 1 diabetes, albiglutide 30 to 50 mg weekly for 1 year had no appreciable effect on preserving residual β-cell function versus placebo.


Re-epithelialisation and the possible involvement of the transcription factor, basonuclin.
This article briefly summarises the basic mechanism of re-epithelialisation and discusses the possible role of the cell-type-specific transcription factor, basonuclin. Re-epithelialisation is initiated by a signal resulting from the absence of neighbouring cells at the wound edge. Basal cells at the wound edge become flattened and lose their intercellular desmosomes and substratum attachment. The amount of cytoplasmic actinomyosin filaments that insert into the new adhesion complexes is increased, and contraction of those filaments produces cell movement. The epithelial cells at the wound edge migrate on a provisional matrix using the newly expressed integrin receptors. Once re-epithelialisation is complete, the epithelial cells revert to the normal phenotype of basal epidermal cells, firmly attach to the newly developed basement membrane zone through hemidesmosomes and resume standard differentiation. Protein synthesis increases in the epidermal cells at the wound edge during re-epithelialisation. Active protein synthesis requires accelerated transcription of ribosomal RNA genes. The transcription factor basonuclin binds to the ribosomal RNA gene promoter and increases the transcription of the genes. Therefore, it is speculated that basonuclin in epithelial cells is required in the process of re-epithelialisation.


Crossover interference and sex-specific genetic maps shape identical by descent sharing in close relatives.
Simulations of close relatives and identical by descent (IBD) segments are common in genetic studies, yet most past efforts have utilized sex averaged genetic maps and ignored crossover interference, thus omitting features known to affect the breakpoints of IBD segments. We developed Ped-sim, a method for simulating relatives that can utilize either sex-specific or sex averaged genetic maps and also either a model of crossover interference or the traditional Poisson model for inter-crossover distances. To characterize the impact of previously ignored mechanisms, we simulated data for all four combinations of these factors. We found that modeling crossover interference decreases the standard deviation of pairwise IBD proportions by 10.4% on average in full siblings through second cousins. By contrast, sex-specific maps increase this standard deviation by 4.2% on average, and also impact the number of segments relatives share. Most notably, using sex-specific maps, the number of segments half-siblings share is bimodal; and when combined with interference modeling, the probability that sixth cousins have non-zero IBD sharing ranges from 9.0 to 13.1%, depending on the sexes of the individuals through which they are related. We present new analytical results for the distributions of IBD segments under these models and show they match results from simulations. Finally, we compared IBD sharing rates between simulated and real relatives and find that the combination of sex-specific maps and interference modeling most accurately captures IBD rates in real data. Ped-sim is open source and available from https://github.com/williamslab/ped-sim.


Redox-dependent domain rearrangement of protein disulfide isomerase from a thermophilic fungus.
Protein disulfide isomerase (PDI) acts as folding catalyst and molecular chaperone for disulfide-containing proteins through the formation, breakage, and rearrangement of disulfide bonds. PDI has a modular structure comprising four thioredoxin domains, a, b, b', and a', followed by a short segment, c. The a and a' domains have an active site cysteine pair for the thiol-disulfide exchange reaction, which alters PDI between the reduced and oxidized forms, and the b' domain provides a primary binding site for substrate proteins. Although the structures and functions of PDI have studied, it is still argued whether the overall conformation of PDI depends on the redox state of the active site cysteine pair. Here, we report redox-dependent conformational and solvation changes of PDI from a thermophilic fungus elucidated by small-angle X-ray scattering (SAXS) analysis. The redox state and secondary structures of PDI were also characterized by nuclear magnetic resonance and circular dichroic spectroscopy, respectively. The oxidized form of PDI showed SAXS differences from the reduced form, and the low-resolution molecular models restored from the SAXS profiles differed between the two forms regarding the positions of the a'-c region relative to the a-b-b' region. The normal mode analysis of the crystal structure of yeast PDI revealed that the inherent motions of the a-b-b' and a'-c regions expose the substrate binding surface of the b' domain. The apparent molecular weight of the oxidized form estimated from SAXS was 1.1 times larger than that of the reduced form, whereas the radius of gyration (ca. 33 A) was nearly independent of the redox state. These results suggest that the conformation of PDI is controlled by the redox state of the active site cysteine residues in the a and a' domains and that the conformational alternation accompanies solvation changes in the active site cleft formed by the a, b, b', and a' domains. On the basis of the results presented here, we propose a mechanism explaining the observed redox-dependent conformational and solvation changes of PDI.


Nicotinic acetylcholine receptor beta2 subunit (CHRNB2) gene and short-term ability to quit smoking in response to nicotine patch.
Genes coding for nicotinic acetylcholine receptors may influence response to nicotine replacement therapy for smoking cessation. We examined the association of a 3' untranslated region polymorphism (rs2072661) in the nicotinic acetylcholine receptor beta2 subunit (CHRNB2) gene with quitting success in response to nicotine versus placebo patch during a short-term test of patch effects. In a within-subjects cross-over design, smokers of European descent (n = 156) received 21 mg nicotine and placebo patch in counter-balanced order, during two separate 5-day simulated quit attempts, each preceded by a week of ad libitum smoking. Abstinence was assessed daily by CO < 5 ppm. Smokers with the CHRNB2 GG genotype had more days of abstinence during the nicotine versus placebo patch week compared with those with the AG or AA genotypes (P < 0.01). Moreover, nicotine patch increased the probability of quitting on the target quit day, quitting anytime during the patch week, and avoiding relapse among those with the GG genotype but not the AA/AG genotypes, although the nicotine x genotype interaction was significant only for quitting on the target quit day (P < 0.05). Regardless of patch condition, quitting on the target quit day was more likely in those with the GG genotype versus AA/AG genotypes (P < 0.05). Genetic associations were not observed for craving or withdrawal responses to nicotine versus placebo patch. These findings are consistent with previous evidence of association of this variant with smoking cessation and suggest that polymorphisms in the nicotinic acetylcholine receptor beta2 subunit gene may influence therapeutic responsiveness to cessation medications.


Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer.
Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain. This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index and Cochrane Central Register of Controlled Trials were searched from January 1995 until October 2010 for primary studies. Conference abstracts from meetings of the European, American and British Urological Associations were also searched. Costs were obtained from NHS sources and the manufacturer of the robotic system. Economic model parameters and distributions not obtained in the systematic review were derived from other literature sources and an advisory expert panel. Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies of men with clinically localised prostate cancer (cT1 or cT2); outcome measures included adverse events, cancer related, functional, patient driven and descriptors of care. Two reviewers abstracted data and assessed the risk of bias of the included studies. For meta-analyses, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness was assessed using a discrete-event simulation model. The searches identified 2722 potentially relevant titles and abstracts, from which 914 reports were selected for full-text eligibility screening. Of these, data were included from 19,064 patients across one RCT and 57 non-randomised comparative studies, with very few studies considered at low risk of bias. The results of this study, although associated with some uncertainty, demonstrated that the outcomes were generally better for robotic than for laparoscopic surgery for major adverse events such as blood transfusion and organ injury rates and for rate of failure to remove the cancer (positive margin) (odds ratio 0.69; 95% credible interval 0.51 to 0.96; probability outcome favours robotic prostatectomy = 0.987). The predicted probability of a positive margin was 17.6% following robotic prostatectomy compared with 23.6% for laparoscopic prostatectomy. Restriction of the meta-analysis to studies at low risk of bias did not change the direction of effect but did decrease the precision of the effect size. There was no evidence of differences in cancer-related, patient-driven or dysfunction outcomes. The results of the economic evaluation suggested that when the difference in positive margins is equivalent to the estimates in the meta-analysis of all included studies, robotic radical prostatectomy was on average associated with an incremental cost per quality-adjusted life-year that is less than threshold values typically adopted by the NHS (£30,000) and becomes further reduced when the surgical capacity is high. The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction. This study demonstrated that robotic prostatectomy had lower perioperative morbidity and a reduced risk of a positive surgical margin compared with laparoscopic prostatectomy although there was considerable uncertainty. Robotic prostatectomy will always be more costly to the NHS because of the fixed capital and maintenance charges for the robotic system. Our modelling showed that this excess cost can be reduced if capital costs of equipment are minimised and by maintaining a high case volume for each robotic system of at least 100-150 procedures per year. This finding was primarily driven by a difference in positive margin rate. There is a need for further research to establish how positive margin rates impact on long-term outcomes. The National Institute for Health Research Health Technology Assessment programme.


Cloning of two members of the calcitonin-family receptors from stingray, Dasyatis akajei: possible physiological roles of the calcitonin family in osmoregulation.
In cartilaginous fish, two cDNAs encoding calcitonin-family receptors were isolated for the first time from the stingray brain. The open reading frame of one receptor cDNA coded a 525-amino acid protein. The amino acid identity of this receptor to human calcitonin-receptor-like receptor (CRLR) is 64.5%, frog CRLR is 64.7%, and flounder CRLR is 61.2% and this was higher than to human calcitonin receptor (CTR) (46.1%), frog CTR (54.7%), and flounder CTR (48.9%). We strongly suggested that this receptor is a ray CRLR based on phylogenetic analysis. In case of the second receptor, amino acid identity among CRLRs (human 50.5%, frog 50.7%, flounder 48.0%) and CTRs (human 43.2%, frog 49.1%, flounder 41.8%) was similar. From phylogenetic analysis of both CRLRs and CTRs, we believe that this receptor is ray CTR. The expression of ray CRLR mRNA was predominantly detected in the nervous system (brain) and vascular system (atrium, ventricle, and gill), which reflects the similar localization of CGRP in the nervous and vascular systems as mammals. It was observed that the second receptor was expressed in several tissues, namely cartilage, brain, pituitary gland, gill, atrium, ventricle, pancreas, spleen, liver, gall bladder, intestine, rectal gland, kidney, testis and ovary. This localization pattern was very similar to flounder CTR. Both receptor mRNAs were strongly expressed in the gill. This suggests that the calcitonin-family members are involved in the osmoregulation of stingray as this fish is known to be euryhaline. When a stingray was transferred to diluted seawater (20% seawater), the expression of both receptors significantly decreased in the gill. Similar results were obtained in the kidney of the stingray. Thus, our cloning and isolation of both receptors in the stingray will be helpful for elucidation of their physiological role(s) such as osmoregulation including calcium metabolism of cartilaginous fish.


Gentamicin Reduces Calcific Nodule Formation by Aortic Valve Interstitial Cells In Vitro.
Gentamicin is a widely employed antibiotic, but may reduce calcium uptake by eukaryotic cells. This study was conducted to determine whether gentamicin reduces calcification by porcine aortic valvular interstitial cells (pAVICs) grown in 2D culture, which is a common model for calcific aortic valve disease (CAVD). The presence of gentamicin (up to 0.2 mM) in the medium of pAVICs cultured for 8 days significantly lowered calcification and alkaline phosphatase content in a dose-dependent manner compared to pAVICs cultured without gentamicin. Gentamicin also significantly increased cell proliferation and apoptosis at concentrations of 0.1-0.2 mM. Next, gentamicin was applied to previously calcified pAVIC cultures (grown for 8 days) to determine whether it could stop or reverse the calcification process. Daily application of gentamicin for 8 additional days significantly reduced calcification to below the pre-calcification levels. These results confirm that gentamicin should be used cautiously with in vitro studies of calcification, and suggest that gentamicin may have the ability to reverse calcification by pAVICs. Given the nephrotoxicity and ototoxicity of this antibiotic, its clinical potential for the treatment of calcification in heart valves is limited. However, further investigation of the pathways through which gentamicin alters calcium uptake by valvular cells may provide insight into novel therapies for CAVD.


Targeted neurorehabilitation strategies in post-stroke aphasia.
Aphasia is a debilitating language impairment, affecting millions of people worldwide. About 40% of stroke survivors develop chronic aphasia, resulting in life-long disability. This review examines extrinsic and intrinsic neuromodulation techniques, aimed at enhancing the effects of speech and language therapies in stroke survivors with aphasia. We discuss the available evidence supporting the use of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation, and functional MRI (fMRI) real-time neurofeedback in aphasia rehabilitation. This review systematically evaluates studies focusing on efficacy and implementation of specialized methods for post-treatment outcome optimization and transfer to functional skills. It considers stimulation target determination and various targeting approaches. The translation of neuromodulation interventions to clinical practice is explored, emphasizing generalization and functional communication. The review also covers real-time fMRI neurofeedback, discussing current evidence for efficacy and essential implementation parameters. Finally, we address future directions for neuromodulation research in aphasia. This comprehensive review aims to serve as a resource for a broad audience of researchers and clinicians interested in incorporating neuromodulation for advancing aphasia care.


The association between bulk tank milk analysis for raw milk quality and on-farm management practices.
Our objective was to determine the risk factors associated with bacteriological quality of bulk tank milk. Bulk tank milk samples were collected from all Prince Edward Island dairy herds (n=235) from March 2005 to March 2007. Biweekly total bacterial, preliminary incubation, laboratory pasteurization, and coliform counts were conducted using a Petrifilm culture system. Data for on-farm risk factors were collected via a mail-out survey which consisted of 4 main sections: (1) general farm demographics and management, (2) cow cleanliness and hygiene, (3) milking procedures and mastitis control, and (4) equipment maintenance and cleaning. Of 235 producers, 153 completed the mail-out survey giving a response rate of 65%. Both total aerobic and preliminary incubation counts were positively associated with the amount of soiling on the teats prior to udder preparation, manual cleaning of the bulk tank, and the use of a specific type of detergent. Additionally, various methods of premilking udder preparation were important, with pre-dip followed by drying being superior to other methods in reducing the bacterial counts. The laboratory pasteurization count was positively associated with the presence of a plate cooler and inadequate frequency of acid wash, whereas having a water purification system was negatively associated with laboratory pasteurization count. Finally, coliform count was negatively associated with clipping udder hair and automated washing of the bulk tank, whereas increasing herd size and inadequate frequency of acid wash were risk factors. Season was a significant predictor for all bacterial counts with the lowest counts tending to occur in winter.


[Distribution and density of two holothurian species in Cubagua Island, Venezuela].
Holothurian populations in the Caribbean have been significantly depleted in some areas, and others are still in danger to satisfy international markets. In Venezuela, this marine resource has been illegally exploited since the early 1990s. To contribute with their management and protection, this work analyzed the distribution, abundance and population structure of two commercial holothurians Isostichopus badionotus and Holothuria mexicana in Cubagua Island shores. A total of 52 stations were studied around the island during the year 2008. Surveys included visits to each station, for which a band transect of 50 m2 with four replicates were carried out. The results show that I. badionotus has a higher distribution on the East coast of the island, and is found over Thalassia testudinum beds or bivalve molluscs aggregations, with an average density of 0.011 ind/m2, C.I. 95% = 0.005-0.017, n = 122, and a general abundance estimated in 117 ind/ha. H. mexicana has been practically depleted (0.001 ind/m2 C.I. 95% = 0.0002-0.0013, 7.7 ind/ha, n = 8). We recommend the maintenance of the total ban adopted in 1997 to assure the protection of these species, mainly because no previous data supported the start of the fishery, and also, because the current densities are still very low when compared to other areas in Venezuela and the Caribbean. These are animals easy to catch, susceptible to overfishing, and with a very low recovery rate; thus, more control is required from the local authorities.


Reduced cortical complexity in children with Prader-Willi Syndrome and its association with cognitive impairment and developmental delay.
Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with symptoms involving not only hypothalamic, but also a global, central nervous system dysfunction. Previously, qualitative studies reported polymicrogyria in adults with PWS. However, there have been no quantitative neuroimaging studies of cortical morphology in PWS and no studies to date in children with PWS. Thus, our aim was to investigate and quantify cortical complexity in children with PWS compared to healthy controls. In addition, we investigated differences between genetic subtypes of PWS and the relationship between cortical complexity and intelligence within the PWS group. High-resolution structural magnetic resonance images were acquired in 24 children with genetically confirmed PWS (12 carrying a deletion (DEL), 12 with maternal uniparental disomy (mUPD)) and 11 age- and sex-matched typically developing siblings as healthy controls. Local gyrification index (lGI) was obtained using the FreeSurfer software suite. Four large clusters, two in each hemisphere, comprising frontal, parietal and temporal lobes, had lower lGI in children with PWS, compared to healthy controls. Clusters with lower lGI also had significantly lower cortical surface area in children with PWS. No differences in cortical thickness of the clusters were found between the PWS and healthy controls. lGI correlated significantly with cortical surface area, but not with cortical thickness. Within the PWS group, lGI in both hemispheres correlated with Total IQ and Verbal IQ, but not with Performance IQ. Children with mUPD, compared to children with DEL, had two small clusters with lower lGI in the right hemisphere. lGI of these clusters correlated with cortical surface area, but not with cortical thickness or IQ. These results suggest that lower cortical complexity in children with PWS partially underlies cognitive impairment and developmental delay, probably due to alterations in gene networks that play a prominent role in early brain development.


Measuring response saturation in human MT and MST as a function of motion density.
The human brain areas MT and MST have been studied in great detail using fMRI with regards to their motion processing properties; however, to what extent this corresponds with single cell recordings remains to be fully described. Average response over human MT+ has been shown to increase linearly with motion coherence, similar to single cell responses. In response to motion density some single cell data however suggest a rapid saturation. We ask how the combination of these responses is reflected in the population response. We measured the blood oxygen level dependent (BOLD) response function of MT and MST using a motion density signal, comparing with area V1. We used spatially fixed apertures containing motion stimuli to manipulate the area covered by motion. We found that MT and MST responded above baseline to a very minimal amount of motion and showed a rather flat response to motion density, indicative of saturation. We discuss how this may be related to the size of the receptive fields and inhibitory interactions, although necessarily residual attention effects also need to be considered. We then compared different types of motion and found no difference between coherent and random motion at any motion density, suggesting that when combining response over several motion stimuli covering the visual field, a linear relationship of MT and MST population response as a function of motion coherence might not hold.


A mathematical model of the intracellular replication and within host evolution of hepatitis type B virus: Understanding the long time course of chronic hepatitis.
Hepatitis B virus (HBV) causes acute and chronic liver disease. Especially, chronic hepatitis is a major risk factor of liver cirrhosis and hepatocellular carcinoma. Viral kinetics of HBV observed in peripheral blood is quite different depending on the clinical course of hepatitis. But the relationship between the intracellular replication dynamics and clinical course of HBV infection is unclear. Further it is very difficult to predict the long time course of hepatitis because the nature of HBV is changed by mutation within host with high mutation rate. We investigate the intracellular replication dynamics and within host evolution of HBV by using a mathematical model. Two different intracellular replication patterns of HBV, "explosive" and "arrested", are switched depending on the viral gene expression pattern. In the explosive replication, prominent growth of HBV is observed. On the other hand, the virion production is restricted in the arrested replication. It is suggested that the arrested and explosive replication is associated with chronic hepatitis and exacerbation of hepatitis respectively. It is shown by our evolutionary simulation that the exacerbation of hepatitis is caused by the emergence of explosive genotype of HBV from arrested genotype by mutation during chronic hepatitis. It is also shown that chronic infection without exacerbation is maintained by short waiting time for virion release and superinfection with arrested genotype. It is suggested that extension of waiting time for virion release and existence of uninfected hepatocyte in the liver may become risk factors for the exacerbation of hepatitis.


Acute myocardial infarction after prednisolone administration for the treatment of anaphylaxis caused by a wasp sting.
Wasp stings have been demonstrated to cause a wide spectrum of allergic reactions from localised reactions to anaphylaxis. Acute coronary syndromes have been described as potential complications of anaphylactic reactions or some of the drugs used for the treatment of anaphylaxis. We know of only a few cases reported of acute myocardial infarction (MI) following corticosteroid administration or anaphylaxis in subjects with normal coronary arteries. If it exists, underlying subclinical coronary atherosclerosis may become clinically evident. A 20 year-old male with anaphylaxis due to a wasp sting, complicated by acute ST-elevation MI after intravenous methyl prednisolone administration, is the subject of this report. He was admitted to our emergency service for dizziness, blurred vision, presyncope and mild respiratory distress 10 minutes after the wasp had stung him on the nape of the neck. Six to seven minutes after administration of prednisolone, the patient complained of typical chest pains. A high posterolateral MI with mild mitral regurgitation were seen on examination. He was treated conservatively with aspirin and heparine. Coronary angiography and intravascular ultrasound imaging, performed 10 days later, showed no evidence of obstructive coronary artery disease. Although reduced coronary perfusion, local histamine release-induced coronary vasospasm or severe hypoxia have been suggested, the pathophysiology remains unclear. Acute STEMI may be a rare but clinically important complication of a wasp sting, anaphylaxis or the corticosteroid used for its treatment, even in young adults with normal coronary arteries. Therefore, physicians should be aware of such serious complications in order to diagnose them early.


Acculturation Associated with Sleep Duration, Sleep Quality, and Sleep Disorders at the US-Mexico Border.
Sleep disparities exist among Hispanics/Latinos, although little work has characterized individuals at the United States (US)-Mexico border, particularly as it relates to acculturation. This study examined the association of Anglo and Mexican acculturation to various facets of sleep health among those of Mexican descent at the US-Mexico border. Data were collected from N = 100 adults of Mexican descent in the city of Nogales, Arizona (AZ). Surveys were presented in English or Spanish. Acculturation was assessed with the Acculturation Scale for Mexican-Americans (ARSMA-II). Insomnia was assessed with the Insomnia Severity Index (ISI), sleepiness was assessed with the Epworth Sleepiness Scale (ESS), sleep apnea risk was assessed with the Multivariable Apnea Prediction (MAP) index, weekday and weekend sleep duration and efficiency were assessed with the Sleep Timing Questionnaire, sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI), and sleep duration and sleep medication use were assessed with PSQI items. No associations were found between Mexican acculturation and any sleep outcomes in adjusted analyses. Anglo acculturation was associated with less weekend sleep duration and efficiency, worse insomnia severity and sleep quality, and more sleep apnea risk and sleep medication use. These results support the idea that sleep disparities may depend on the degree of acculturation, which should be considered in risk screening and interventions.


Description of the methodology used in an ongoing pediatric care interventional study of children born with cleft lip and palate in South America [NCT00097149].
The contribution of birth defects, including cleft lip and palate, to neonatal and infant mortality and morbidity is substantial. As other mortality and morbidity causes including infections, hygiene, prematurity, and nutrition are eradicated in less developed countries, the burden of birth defects will increase proportionally. We are using cleft lip and palate as a sentinel birth defect to evaluate its burden on neonatal and infant health and to assess the effectiveness of systematic pediatric care during the first month and first two years of life in decreasing this burden. The neonatal intervention, consisting of weekly pediatric evaluation and referral to appropriate care, is delivered to about 696 infants born with cleft lip and/or palate in 47 hospitals in South America. Neonatal mortality in this group will be compared to that in a retrospective control group of about 464 infants born with cleft lip and/or palate in the same hospitals. The subgroup of infants with isolated clefts of both the lip and palate (about 264) is also randomized into two groups, intervened and non-intervened, and further followed up over 2 years. Intervened cases are evaluated by pediatricians every three months and referred for appropriate care. The intervened and non-intervened cases will be compared over study outcomes to evaluate the intervention effectiveness. Non-intervened cases are matched and compared to healthy controls to assess the burden of cleft lip and palate. Outcomes include child's neurological and physical development and family social and economic conditions. Large-scale clinical trials to improve infant health in developing countries are commonly suggested, making it important to share the methods used in ongoing studies with other investigators implementing similar research. We describe here the content of our ongoing pediatric care study in South America. We hope that this may help researchers targeting this area to plan their studies more effectively and encourage the development of similar research efforts to target other birth defects or infant outcomes such as prematurity and low birth weight.


Training the next generation of global health advocates through experiential education: A mixed-methods case study evaluation.
This case study evaluates a global health education experience aimed at training the next generation of global health advocates. Demand and interest in global health among Canadian students is well documented, despite the difficulty in integrating meaningful experiences into curricula. Global health advocacy was taught to 19 undergraduate students at McMaster University through an experiential education course, during which they developed a national advocacy campaign on global access to medicines. A quantitative survey and an analysis of social network dynamics were conducted, along with a qualitative analysis of written work and course evaluations. Data were interpreted through a thematic synthesis approach. Themes were identified related to students' learning outcomes, experience and class dynamics. The experiential education format helped students gain authentic, real-world experience in global health advocacy and leadership. The tangible implications for their course work was a key motivating factor. While experiential education is an effective tool for some learning outcomes, it is not suitable for all. As well, group dynamics and evaluation methods affect the learning environment. Real-world global health issues, public health practice and advocacy approaches can be effectively taught through experiential education, alongside skills like communication and professionalism. Students developed a nuanced understanding of many strategies, challenges and barriers that exist in advocating for public health ideas. These experiences are potentially empowering and confidence-building despite the heavy time commitment they require. Attention should be given to how such experiences are designed, as course dynamics and grading structure significantly influence students' experience.


Elevated cytomegalovirus IgG antibody levels are associated with HIV-1 disease progression and immune activation.
To assess the association between cytomegalovirus (CMV) IgG antibody levels, HIV disease progression, and immune activation markers. A prospective cohort study was conducted among women enrolled in a trial that was designed to determine the effect of acyclovir on HIV disease progression in Rakai, Uganda. The primary endpoints were progression to a CD4 T-cell count less than 250 cells/μl, nontraumatic death, or initiation of antiretroviral therapy (ART). CD4 T-cell counts, HIV viral load, C-reactive protein (CRP), and soluble CD14 levels were assessed biannually for 24 months. CMV IgG antibodies were measured at baseline among all women and annually among a subset of women who initiated ART. There were 300 HIV/CMV-coinfected participants who contributed a total of 426.4 person-years with a median follow-up time of 1.81 years. Compared with the lowest CMV IgG tertile group at baseline, the highest CMV IgG tertile group was associated with an increased risk to reach a primary endpoint independent of acyclovir use, age, CD4 T-cell count, and HIV viral load at baseline [adjusted hazard ratio = 1.59; (95% CI = 1.05-2.39); P = 0.027]. Among pre-ART visits (n = 1200), women in the highest baseline CMV IgG tertile had increasing annual rates of soluble CD14 and CRP levels, which was not observed for the low CMV IgG tertile group. Compared with pre-ART visits, CMV IgG antibody levels were higher post-ART initiation, and concurrent levels remained associated with soluble CD14 and CRP during suppressive ART (n = 88 person-visits). The magnitude of the immune response to CMV was associated with HIV disease progression and immune activation in sub-Saharan Africa.


Segregated neural representation of psychological and somatic-vegetative symptoms in severe major depression.
The Beck Depression Inventory (BDI) is probably the most widely used depression scale. It has been suggested that it contains a two-factor structure measuring cognitive-affective (i.e. psychological) and somatic-vegetative depressive symptoms. In this study we aim to evaluate these factors by probing for their neural correlates. Neural responses evoked by emotional perception, relative to an emotional judgment task, were measured using functional magnetic resonance imaging (fMRI) in 20 medication-free patients with severe MDD. Psychological and somatic-vegetative symptoms were evaluated with the BDI. Psychological symptoms correlated with signal changes in the dorsomedial and right ventrolateral prefrontal cortex, while somatic-vegetative symptoms correlated with signal changes in the pre-genual anterior cingulate cortex. These preliminary findings demonstrate segregated neural representation of psychological and somatic-vegetative symptoms of MDD in different cortical regions. Thus, our results indicate that the two-factor structure of the BDI is related to distinct neural correlates.


Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.
The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.


The effect of distress on the balance between goal-directed and habit networks in obsessive-compulsive disorder.
The classical cognitive-behavioral theory of obsessive-compulsive disorder (OCD) holds that compulsions are performed to reduce distress that is evoked by obsessions, whereas a recent neuroscience-inspired theory suggests that compulsivity results from a disbalance between goal-directed and habit-related neural networks. To bridge these theories, we investigated whether the balance between goal-directed and habit networks in patients with OCD was affected during psychological distress. Twenty-three OCD patients and twenty-three healthy controls participated in a controlled stress induction paradigm using the socially evaluated cold-pressor test in a crossover design. Stress responses were evaluated through cortisol levels, blood pressure, and anxiety ratings. Functional connectivity of the caudate nucleus and posterior putamen was assessed using seed region analysis of resting-state functional magnetic resonance imaging data, which are hubs of the goal-directed and habit network, respectively. Stress induction increased blood pressure and psychological stress measures across groups and resulted in blunted cortisol responses in patients. Furthermore, patients showed a blunted reduction in connectivity between the caudate nucleus and precuneus during psychological distress, which was positively correlated with compulsivity but not obsession severity. The posterior putamen showed no significant group differences in distress-induced connectivity. These results suggest that compulsivity in OCD is associated with altered connectivity between the goal-directed and default mode networks during psychological distress.


Upregulation of GPR109A in Parkinson's disease.
Anecdotal animal and human studies have implicated the symptomatic and neuroprotective roles of niacin in Parkinson's disease (PD). Niacin has a high affinity for GPR109A, an anti-inflammatory receptor. Niacin is also thought to be involved in the regulation of circadian rhythm. Here we evaluated the relationships among the receptor, niacin levels and EEG night-sleep in individuals with PD. GPR109A expression (blood and brain), niacin index (NAD-NADP ratio) and cytokine markers (blood) were analyzed. Measures of night-sleep function (EEG) and perceived sleep quality (questionnaire) were assessed. We observed significant up-regulation of GPR109A expression in the blood as well as in the substantia nigra (SN) in the PD group compared to age-matched controls. Confocal microscopy demonstrated co-localization of GPR109A staining with microglia in PD SN. Pro and anti-inflammatory cytokines did not show significant differences between the groups; however IL1-β, IL-4 and IL-7 showed an upward trend in PD. Time to sleep (sleep latency), EEG REM and sleep efficiency were different between PD and age-matched controls. Niacin levels were lower in PD and were associated with increased frequency of experiencing body pain and decreased duration of deep sleep. The findings of associations among the GPR109A receptor, niacin levels and night-sleep function in individuals with PD are novel. Further studies are needed to understand the pathophysiological mechanisms of action of niacin, GPR109A expression and their associations with night-sleep function. It would be also crucial to study GPR109A expression in neurons, astrocytes, and microglia in PD. A clinical trial to determine the symptomatic and/or neuroprotective effect of niacin supplementation is warranted.


Does confirmed pathogen transfer between sanctuary workers and great apes mean that reintroduction should not occur? Commentary on "Drug-resistant human Staphylococcus aureus findings in sanctuary apes and its threat to wild ape populations".
This commentary discusses the findings and conclusions of the paper "Drug resistant human Staphylococcus aureus findings in sanctuary apes and its threat to wild ape populations." This paper confirms the zoonotic transfer of Staphylococcus aureus in a sanctuary setting. The assertion that this in itself is enough to reconsider the conservation potential of ape reintroduction provides an opportunity to discuss risk analysis of pathogen transmission, following IUCN guidelines, using S. aureus as an example. It is concluded that ape reintroduction projects must have disease risk mitigation strategies that include effective biosecurity protocols and pathogen surveillance. These strategies will assist with creating a well planned and executed reintroduction. This provides one way to enforce habitat protection, to minimise human encroachment and the risks from the illegal wildlife trade. Thus reintroduction must remain a useful tool in the conservation toolbox.


Lipid levels among African and Middle-Eastern Bedouin populations.
Previous studies observed higher high-density lipoprotein (HDL) levels and lower triglycerides levels among people of African ancestry. The goal of this study was to characterize lipid levels in Bedouins of African vs. Middle-Eastern ethnicity. A cross-sectional study was conducted in a Bedouin primary care clinic in southern Israel, with 4470 listed individuals over the age of 21, of whom 402 (9%) were of African origin. A stratified random sample was included in the analysis. Associations between ethnicity, age, gender and lipid levels were assessed. Multiple linear regression and logistic regression models were used for multivariate analysis. The study included 261 African Bedouins and 406 Middle-Eastern Bedouins. (median age: 37 years, 58.6% females). The average total cholesterol and low-density lipoprotein (LDL) levels were 10 mg/dl lower among African Bedouins as compared to Middle-Eastern Bedouins (total cholesterol: 168.6 vs. 179.6 mg/dl, p<0.001; LDL: 99.5 vs. 109.0 mg/dl, respectively, p<0.001). Average triglycerides levels were 36 mg/dl lower among African Bedouins as compared to Middle-Eastern Bedouins (102.8 vs. 138.9 mg/dl, respectively, p<0.001). Average HDL levels were 3 mg/dl higher among African Bedouins as compared to Middle-Eastern Bedouins (48.3 vs. 44.6 mg/dl, respectively, p<0.001). A lower prevalence of dyslipidemia was found in African Bedouins, as compared with Middle-Eastern Bedouins.


Management of hereditary angioedema in pediatric patients.
Hereditary angioneurotic edema is a rare disorder caused by the congenital deficiency of C1 inhibitor. Recurring angioedematous paroxysms that most commonly involve the subcutis (eg, extremities, face, trunk, and genitals) or the submucosa (eg, intestines and larynx) are the hallmarks of hereditary angioneurotic edema. Edema formation is related to reduction or dysfunction of C1 inhibitor, and conventional therapy with antihistamines and corticosteroids is ineffective. Manifestations occur during the initial 2 decades of life, but even today there is a long delay between the onset of initial symptoms and the diagnosis of hereditary angioneurotic edema. Although a variety of reviews have been published during the last 3 decades on the general management of hereditary angioneurotic edema, little has been published regarding management of pediatric hereditary angioneurotic edema. Thus, we review our experience and published data to provide an approach to hereditary angioneurotic edema in childhood.


NADPH oxidase: a target for the modulation of the excessive oxidase damage induced by overtraining in rat neutrophils.
The purpose of this study is to demonstrate that NADPH oxidase mediating the ROS production is the major pathway for ROS generation in neutrophils during exercise. NADPH oxidase, as a target can modulate oxidative damage induced by overtraining, which can be value to the prevention of exercise-induced immunosuppression. Thirty male Wistar rats were randomly divided into three groups: a negative control group (C, n = 10), an overtraining group (E, n = 10) and an overtraining + DPI intervention group (D, n =10). Groups E and D were trained on a standard treadmill with progressive load for 11 weeks. After 36-40 h from the last training, eight rats were randomly selected from each group, and blood was sampled from the orbital vein. ELISAs were used to measure serum cytokine levels and lipid peroxidation in blood plasma. Flow cytometry with Annexin V/PI double staining was used to measure neutrophil apoptosis and necrosis. DNA damage in lymphocytes was tested using single cell gel electrophoresis (SCGE). The co-localization between gp91(phox) and p47(phox) of the NADPH-oxidase was detected using immunocytochemistry and confocal microscopy. 1) Compared with group C, the concentrations of IL-1β, IL-8, and TNF-α were significantly increased and MCP-1, and CINC were significantly decreased in blood plasma from group E (P < 0.01 and P < 0.05, respectively). Concentrations of IL-1β and MCP-1 were decreased (P < 0.05), and IL-8 and TNF-α were significantly increased (P <0.05) in blood plasma from group D. MDA and MPO were elevated in plasma from groups E and D (P < 0.01 and P < 0.05, respectively). 2) Compared with group C, the percentage of neutrophils apoptosis were significantly elevated (P < 0.01) in both groups E and D, and the percentage of cell death was raised in group E (P < 0.05). No significant change was observed in group D. 3) Compared with group C, the number of comet cells, an indicator of DNA damage, was significantly increased (P < 0.01), and the width and tail length of comet cells were notably increased in group E, while no significant increase was observed in group D. 4) The p47(phox )protein translocated to the cell membrane and co-localized with the gp91(phox) subunit of NADPH oxidase in neutrophils activated by overtraining. 1) Excessive exercise led to an increased secretion of inflammatory cytokines and chemokines in peripheral blood, and it may have induced tissue inflammation 2) Overtraining can activate the NADPH oxidase-mediated overproduction of ROS, leading to increased lipid peroxidation. 3) NADPHoxidase in neutrophils as a target, was responsible for ROS, oxidative damage to phagocytes and lymphocytes and changes to inflammatory cytokines and immune regulatory factors all affect cellular immune functions and may be causative factors for exercise-induced immunosuppression.


"Something Born of the Heart": Culturally Affiliated Illnesses of Older Adults in Oaxaca.
This qualitative research identifies and analyzes emotions and interventions linked to affective experiences and cultural aspects of health/illness/care processes in 219 older adults of eight Indigenous groups in Oaxaca, Mexico. Life stories are examined from perspectives of cultural gerontology, anthropology of emotions and critical medical anthropology with a gender perspective. Significance and healing of two illnesses of cultural affiliation: tiricia (sadness of the soul) and envidia (rancor against the successful) are examined. Conditions other than diabetes and hypertension are healed by traditional remedies or spiritual cleansings. Examining tiricia and envidia permit improved knowledge and understanding of the emotional culture and the community.


Epidermal growth factor receptor R521K polymorphism shows favorable outcomes in KRAS wild-type colorectal cancer patients treated with cetuximab-based chemotherapy.
The R521K polymorphism of epidermal growth factor receptor has attenuated affinity in ligand binding and proto-oncogene induction, which may affect the efficacy of cetuximab. We analyzed the effect of this polymorphism on the outcome of 112 patients with KRAS wild-type metastatic colorectal carcinoma treated with first-line cetuximab plus FOLFOX-4. The associations of this polymorphism with vascular endothelial growth factor (VEGF) expression and clinicopathologic characteristics were also examined. The results showed that the frequencies of the G/G, G/A, and A/A genotypes were 32.1% (n = 36), 42.9% (n = 48), and 25.0% (n = 28), respectively. A marked decrease in VEGF expression levels (66.7% vs 28.9%, P < 0.01) was observed in patients with 521A allele variants (Arg/Lys or Lys/Lys), which were associated with a decreased tumor size (55.6% vs 31.6%, P = 0.02), good histological differentiation (63.9% vs 85.5%, P = 0.01), decreased lymphovascular invasion (69.4% vs 39.5%, P < 0.01), and a higher response rate to cetuximab plus FOLFOX treatment (55.6% vs 78.9%, P = 0.01). In addition, this polymorphism was associated with a longer progression-free period (P = 0.001) and overall survival (P = 0.001). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor. These data suggest that the R521K polymorphism of epidermal growth factor receptor, by reducing its activation and a consequential downregulation of its target genes, including VEGF, could be a key determinant of an increased response to cetuximab-based chemotherapy and a longer survival for KRAS wild-type colorectal carcinoma patients.


Positive relationships between association strength and phenotypic similarity characterize the assembly of mixed-species bird flocks worldwide.
Competition theory predicts that local communities should consist of species that are more dissimilar than expected by chance. We find a strikingly different pattern in a multicontinent data set (55 presence-absence matrices from 24 locations) on the composition of mixed-species bird flocks, which are important subunits of local bird communities the world over. By using null models and randomization tests followed by meta-analysis, we find the association strengths of species in flocks to be strongly related to similarity in body size and foraging behavior and higher for congeneric compared with noncongeneric species pairs. Given the local spatial scales of our individual analyses, differences in the habitat preferences of species are unlikely to have caused these association patterns; the patterns observed are most likely the outcome of species interactions. Extending group-living and social-information-use theory to a heterospecific context, we discuss potential behavioral mechanisms that lead to positive interactions among similar species in flocks, as well as ways in which competition costs are reduced. Our findings highlight the need to consider positive interactions along with competition when seeking to explain community assembly.


Ideology: Its Resurgence in Social, Personality, and Political Psychology.
We trace the rise, fall, and resurgence of political ideology as a topic of research in social, personality, and political psychology. For over 200 years, political belief systems have been classified usefully according to a single left-right (or liberal-conservative) dimension that, we believe, possesses two core aspects: (a) advocating versus resisting social change and (b) rejecting versus accepting inequality. There have been many skeptics of the notion that most people are ideologically inclined, but recent psychological evidence suggests that left-right differences are pronounced in many life domains. Implicit as well as explicit preferences for tradition, conformity, order, stability, traditional values, and hierarchy-versus those for progress, rebelliousness, chaos, flexibility, feminism, and equality-are associated with conservatism and liberalism, respectively. Conservatives score consistently higher than liberals on measures of system justification. Furthermore, there are personality and lifestyle differences between liberals and conservatives as well as situational variables that induce either liberal or conservative shifts in political opinions. Our thesis is that ideological belief systems may be structured according to a left-right dimension for largely psychological reasons linked to variability in the needs to reduce uncertainty and threat.


Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) Diet Slows Cognitive Decline After Stroke.
This study sought to determine if the MIND diet (a hybrid of the Mediterranean and Dash diets, with modifications based on the science of nutrition and the brain), is effective in preventing cognitive decline after stroke. We analyzed 106 participants of a community cohort study who had completed a diet assessment and two or more annual cognitive assessments and who also had a clinical history of stroke. Cognition in five cognitive domains was assessed using structured clinical evaluations that included a battery of 19 cognitive tests. MIND diet scores were computed using a valid food frequency questionnaire (FFQ). Dietary components of the MIND diet included whole grains, leafy greens and other vegetables, berries, beans, nuts, lean meats, fish, poultry, and olive oil and reduced consumption of cheese, butter, fried foods, and sweets. MIND diet scores were modeled in tertiles. The influence of baseline MIND score on change in a global cognitive function measure and in the five cognitive domains was assessed using linear mixed models adjusted for age and other potential confounders. With adjustment for age, sex, education, APOE-ε4, caloric intake, smoking, and participation in cognitive and physical activities, the top vs lowest tertiles of MIND diet scores had a slower rate of global cognitive decline (β = .08; CI = 0.0074, 0.156) over an average of 5.9 years of follow-up. High adherence to the MIND diet was associated with a slower rate of cognitive decline after stroke.